Cryosurgery has achieved wide acceptance as a clinical procedure and is proving useful for a rapidly increasing range of applications. Among these are the extraction of cataractous lenses of the eye, the repair of detached retinas, the ablation of heart tissue to correct cardiac arrhythmias, and the destruction of tumors in the prostate, liver, brain, and other internal organs. Cryosurgery involves the insertion of a cryoprobe to destroy undesired tissue by highly localized freezing. Once the tissue is frozen, it is allowed to thaw. The body's immune system then gradually decomposes the destroyed tissue and removes it from the body. Cryosurgery offers a number of advantages, including the fact that it is only minimally invasive yet highly controllable, and not dose limited.
Cryoprobes are thin, cylindrical devices that are cooled internally with a cryogen and insulated except at the tip. As the cryogen is circulated through the probe, freezing of the tissue occurs from the tip outward, producing a moving freezing front, or interface between frozen and nonfrozen tissue, that is sharply defined and propagates slowly through the tissue (at rates on the order of millimeters per minute). Relatively large regions can be treated with small probes; a 3-mm diameter probe for example can produce an ice ball 3.5 cm in diameter. When the region of pathological tissue is large and complex in shape, a frozen region corresponding closely to the tissue of interest can be generated by using several probes simultaneously. Multiple sites can be treated either separately or together. Since the insertion of the cryoprobes is the only physical invasion of the tissue, the complications entailed by the procedure and patient morbidity are reduced, and the procedure entails less distress to and disfiguration of the patient, all while achieving the therapeutic result at a lower cost than traditional invasive surgery.
One of the limitations of cryosurgery is the danger of freezing less than all of the undesired tissue, or the freezing of a substantial amount of healthy tissue adjacent to the undesired tissue. With recent advances in non-invasive medical imaging technology, however, under-freezing and over-freezing are much less of a danger. Intraoperative ultrasound imaging, for example, can be used to monitor the location of the freezing front and hence the size, shape and location of the frozen tissue, by virtue of the change in acoustic impedance between frozen and unfrozen tissue. Magnetic resonance imaging has also been used effectively, and offers the advantage of imaging the location of the freezing front in three dimensions with a resolution of 200 .mu.m.
Imaging has revealed a further limitation, however: the freezing of living cells under certain conditions can preserve the cells rather than destroy them. An explanation of when preservation occurs rather than destruction and vice versa is found in the "two factor" (i.e., chemical and mechanical) theory proposed by Mazur, P., in "Cryobiology: The Freezing of Biological Systems," Science 168:939-949 (1970). This theory recognizes that the probability for an ice crystal to form at any given temperature is a function of volume, with the probability being higher in a larger volume. In a cellular suspension, the result of this effect is that ice will form first in the extracellular space since this space is much larger than the volume inside an individual cell. As the extracellular ice forms, the concentration of solutes in the remaining unfrozen solution rises, surrounding the cells with a hypertonic solution. This occurs while the intracellular fluid is still in liquid form, creating a chemical potential across the cell membrane. This causes water to pass through the membrane from the cell interior outward, leaving ions and organic solutes (to which the membrane is impermeable) inside the cell. The cell thus dehydrates and becomes hypertonic itself, which leads to cell death by chemical damage. Chemical damage however is a function of time and temperature, and water transport across the cell membrane is a rate-dependent process. Thus, lower cooling rates will increase the probability of chemical damage by allowing more time for exposure of the cell to hypertonic conditions. Conversely, ice formation within the cell itself is believed to cause cell death by mechanical damage, and increasing the cooling rate above a certain level causes ice nucleation inside the cell before the water can migrate outward. In the high cooling rate regime, therefore, the probability for intracellular ice formation and the consequential cell death increases, rather than decreases, with increasing cooling rate. The two conflicting modes of cell destruction result in a inverse U-shaped curve for the cell survival rate vs. the cooling rate. In addition to the cooling rate, other factors thought to affect the cell survival rate are the temperature gradient, the speed at which the freezing interface advances, the final freezing temperature, the holding time at that temperature, the warming rate subsequent to freezing, and the number of freeze-thaw cycles involved.
In cryosurgery, these parameters are particularly difficult to control since temperature control is achieved only at the tip of the probe and the composition of the surrounding tissue is not necessarily uniform. Variations in one or more of the freezing parameters will occur throughout the treated area during the course of a single procedure, since the continuously increasing size of the frozen region causes different parts of the tissue to experience different cooling rates, different final freezing temperatures and different holding times, depending on the distance of these parts from the probe tip. In addition, the manner of performing the procedure will vary between physicians as well as between clinics. As a result, the outcome of the typical cryosurgical procedure is often unpredictable and difficult to control.